Today, about 2 billion people carry serological markers of HBV. About 400 million of them are chronically infected with HBV. According to the center of disease control (CDC) 15-25% of chronically HBV infected people are prone to develop hepatocellular carcinoma (HCC) within a decade if they do not receive appropriate treatment (1). HBV-related HCC has a poor prognosis and HBV has therefore been classified by the world health organization (WHO) as the most important naturally occurring human carcinogen. Despite the existence of a prophylactic vaccine, the number of infections will rise in the upcoming decades due to the increasing world population and the limitation of prophylaxis in the poor countries.
In industrial countries HBV is primarily transmitted via the parenteral route. 90-95% of the acutely infected, immuno competent individuals clear the virus, thereby gaining life long immune protection. About 5-10% of them develop chronic Hepatitis B (300,000-500,000 persons in Germany). In contrast, in high endemic areas, particularly Central Africa and Eastern Asia, the main mode of transmission is vertically from mother to child. Unfortunately, infection of not fully immunocompetent children results in a 90-98% chronic course of the disease. Hepatitis B-related HCC is therefore the most common malignancy in many of these countries.
Currently approved therapeutic regiments for the treatment of chronic hepatitis B virus (HBV) infections either address replication steps of the viral genome after an already established infection (Lamivudine, Adefovir, Entecavir) or act as modulators of the immune system (interferon alpha). Unfortunately, only 10-25% of the patients preserve a sustained virological response upon such therapies, reflecting—inter alia—the fast selection of nucleo(s)tide resistant mutants. Despite the availability of a preventative vaccine, it is therefore of utmost importance to develop novel therapeutics that target so far unaffected replication steps e.g. virus entry.
Specific inhibition of virus entry is an attractive therapeutic concept to control and eventually eliminate acute and chronic infections. For HIV, interference with virus entry has been successfully accomplished by a gp41 protein-derived peptide consisting of 36 amino acids (Fuzeon®) which prevents fusion of the viral and the cellular membrane (2).
Despite of the availability of a prophylactic vaccine and reverse transcriptase (RT) inhibitors, the number of HBV-infected people and the number of HBV-related deaths worldwide (presently about 500,000 per year) is increasing. About two thirds of primary liver cancers are attributable to persistent HBV infection (3).
Current treatment pursues two strategies: (i) interferon (IFN alpha) treatment modulates immune responses against HBV and displays a direct antiviral effect, which leads to long-term clinical benefit in about 30% of treated patients without eradication of the virus; (ii) administration of viral reverse transcriptase inhibitors suppresses viral replication and is accompanied by significant biochemical and histological improvements after one year of treatment. However, long-term treatment is associated with the emergence of resistant virus strains (4).
HBV is the prototype of a family of small, enveloped DNA viruses of mammals and birds (5). The HBV envelope encloses three proteins termed L-(large), M-(middle) and S-(small) (see FIG. 1A). They share the C-terminal S-domain with four transmembrane regions. The M- and L-protein carry additional N-terminal extensions of 55 (preS2) and, genotype-dependent, 107 or 118 aa (preS1) (see FIG. 1B). In virions the stoichiometric ratio of L, M and S is about 1:1:4, while the more abundantly secreted non-infectious subviral particles (SVPs) contain almost exclusively S- and only traces of L-protein (6). During synthesis, the preS1-domain of L is myristoylated and translocated through the ER. This modification is essential for HBV infectivity (7, 8).
Studies of the early events of HBV infection have been limited, since neither cell culture systems nor small animal models were available until recently (9). The development of the HBV susceptible cell line HepaRG facilitated systematic investigations of HBV entry and resulted in the discovery of envelope protein-derived entry inhibitors (10).
Furthermore, to date there exists no effective therapy for HDV infection, a satellite virusoid utilizing HBV envelope proteins for the entry into hepatocytes (15, 17, 20). There is a need in the art to provide effective therapies against HDV infection.
Thus, the present invention aims to improve the methods and means for the inhibition, prevention and/or treatment of HBV infection and other HBV-related diseases as present in the prior art and it is, thus, an objective of the present invention to provide improved methods and means which allow for a targeted and effective inhibition, prevention and/or treatment of HBV infection and HBV-related diseases.
It is a further objective of the present invention to provide methods and means for the inhibition, prevention and/or treatment of HDV infection and HDV-reiated diseases.